Chronic wasting disease (CWD) is a prion disorder of elk and deer that is uniformly fatal, exceedingly difficult to control in nature, and has been detected in over 20 states and 2 Canadian provinces. Given that humans, food animals, and wildlife are increasingly exposed to CWD prions, the potential for cross-species CWD transmission is a major concern. Prion transmission occurs when the normal cellular prion protein, PrPC, is converted to a misfolded and infectious isoform called PrPSc. Sequence similarity between host PrPC and infectious PrPSc is a key factor in determining prion susceptibility, however the specific amino acids that control susceptibility to CWD are not clear. Recent studies suggest that a 10-residue loop connecting a ? -strand with an ? -helix (?2-?2 loop) impacts the ease of cross-species prion transmission. Furthermore, crystallography experiments have shown that ?2-?2 loop peptide segments can interact by tightly interlacing their amino acid side chains to form a steric zipper, a structure that may promote protein-misfolding. The central hypothesis of this proposal is that amino acids within the ?2-?2 loop of PrPC support prion conversion and impact cross-species prion transmission. The objectives of these studies are: (1) to solve the structural mechanism underlying human susceptibility or resistance to CWD and other prions, and (2) to define the role of steric zippers in promoting PrPC to PrPSc conversion among different prion conformational variants, known as strains. To accomplish these objectives, this work will use novel transgenic mouse models expressing chimeric forms of human PrPC as well as a highly innovative in vitro prion conversion assay. Dr. Timothy Kurt is a DVM, PhD with nine years of experience studying prion diseases, including CWD. His research interests include the pathogenesis and prevention of protein- misfolding disorders such as prion, Alzheimer's and Parkinson's diseases. Dr. Kurt's primary career goal is to become a principal investigator at an academic biomedical research institution, and the K01 award would support his progress to independence by providing protected time to pursue research with highly supportive mentors. He has assembled an outstanding mentoring and advising team that includes veterinary scientists, pathologists, a structural biologist and a chemist with expertise in amyloid formation. Five years of support is requested.